Numerous macrocyclic peptides and depsipeptides have been isolated from natural sources which complex sodium, potassium, and calcium cations to varying degrees and effect transmembrane transport of such species. Cation transport is important to many biological processes and divalent calcium cation is the physiologic regulator of muscle contraction. In order to better understand the role ionophores play in transport and in the hope of making relatively simple, synthetic ionophores which are both cation selective and biologically active, we propose to prepare novel macrocycles having a variety of ring sizes, sidearms, and Lewis basic donor groups. These compounds will be based on the "lariat ether" concept we have developed and on the information gleaned from basic studies with single-armed, carbon- and nitrogen-pivot compounds. Extensive cation binding constant studies to determine the strength of binding and cation selectivity have provided considerable information and these will be continued. The main effort during the proposed project period will be to prepare two-and three-armed macrocycles which will provide a ring-bound cation with true three-dimensional solvation and which may be useful for transport not only of cations, but of small molecules as well. It is also expected that these novel compounds may have interesting and new chemistry themselves. The design process will take account of polarity, steric effects, chirality, and size relationships. In this way, we hope to obtain selective and biologically active structures which remain synthetically accessible.